Abstract word count: 424 HIV infected adults who drink are already physiologically frail due to HIV infection, comorbidity (including hepatitis C infection), polypharmacy and associated substance use. In this setting, biomedical consequences of alcohol use can occur with moderate use and are often unappreciated or misattributed. The ?Consortium to improve OutcoMes in HIV/Aids, Alcohol, Aging & multi-Substance? (COMpAAAS) is supported by NIH/NIAAA award U24AA020794 to study this issue in a single sample, the Veterans Aging Cohort Study (VACS) (~50,000 HIV+ US veterans demographically matched to ~100,000 uninfected comparators). VACS will employ a direct alcohol biomarker (Phosphatidyl-ethanol (PEth) and a validated measure of physiologic frailty (VACS Index). In this set of three applications, the Antiretroviral Therapy Cohort Collaboration (ART-CC) and Kaiser Permanente (KP) teams join the Veterans Healthcare System (VA) team as COMpAAAS Tripartite: ART-CC, KP, and VA. Our long term goal is to inform alcohol intervention design and implementation. Together we propose to study biomedical consequences of alcohol and associated substance use in HIV extending the scope and generalizability of VACS to multiple healthcare systems in North America and Europe and substantially increasing sample size and diversity of HIV+ subjects. Importantly, COMpAAAS Tripartite also extends uninfected comparators, a critically important group if we are to understand how alcohol may differentially effect biomedical outcomes in HIV. KP will be able to identify appropriate comparators from their Northern California region. A new VA sample of veterans born in 1945-1965 (Birth Cohort) substantially expands access to Hepatitis C infected (HCV+) and women comparators. The tripartite group will also participate in a HIV+ substudy (n=2250), The Medications, Alcohol, Substance Use in HIV Study (MASH), in which new data on potentially inappropriate medications (PIMS) and direct biomarkers for alcohol and associated substances (tobacco, marijuana, opioids, cocaine, and methamphetamine) will be prospectively collected. In initial years, analyses will be conducted using self-report of alcohol and substance use. Limited data sets and uniform methods for data cleaning, standardization, and imputation will be employed across teams. Analyses will be repeated in the final year correcting for biases in self-reported alcohol and substance use based upon MASH results. Consistent with the RFA, all grants contribute data for all aims, have identical aims and protocols, and share data. The VA team will coordinate data sharing and analyses. Each collaborator will be responsible for conducting analyses for one aim. In this application, we will investigate the risk of mortality, hospitalization, and increased physiologic frailty measured by the VACS Index that is attributable to different levels of alcohol use and we will compare these outcomes in HIV-infected and uninfected populations.